17-(hydrocarbon-substituted)-4-oxa-5alpha-androstan-17beta-ols



rats Sept. 25, 1962, Ser. No. 226,168 Claims. c1. zen-345.2

The present invention pertains to novel steroid-like organic compoundscharacterized by an oxygen-containing heterocyclic ring structure, and,more particularly, to 4-oxa-5a-androstan-17B-ols substituted at the17-position also by an aliphatic hydrocarbon group, as is represented bythe structural formula wherein R is a lower hydrocarbon radical.

Examples of the lower hydrocarbon radicals represented by R are alkyl,alkenyl, and alkynyl radicals such as methyl, ethyl, propyl, butyl,pentyl, hexyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, ethynyl,propynyl, butynyl, pentynyl, hexynyl, and the branched-chain isornersthereof.

The compounds of the present invention are conveniently manufactured byutilizing as the starting material, 4-oxa-5oc-androstan-17-one. Thereaction of that substance with an aliphatic organo-metallic reagentaffords the 17-(hydrocarbon-substituted)-17B-ols of this invention.Typically, 4-oxa-5a-androstan-17-one in tetrahydrofuran is allowed toreact with ethereal methyl magnesium bromide, and the resulting adductis hydrolyzed with water to afford 17a-methyl-4-oxa-5a-androstan-175-01. The reaction of that starting material with a lower alkyne in thepresence of a suitable alkaline catalyst, on the other hand, producesthe 17a-(lower alkynyl)- 17B-ols of this invention. When the 10 eralkyne is acetylene and the alkaline catalyst is potassium hydroxide,for example, 17a-ethynyl-4-oxa-5a-androstan-Ufl-ol results. i

The l7a-(l'ower alkenyl) compounds of this invention can be obtained bypartial reduction of the corresponding 17a-(lower alkynyl) compounds. Asa specific example of the process involved, the aforementionedl7a-ethynyl- 4-oxa-5a-androstan-17fi-ol in pyridine is shaken withhydrogen in the presence of a 5% palladium-on-calcium carbonate catalystto yield 17a-vinyl-4-oxa-5ct-androstan- 173-01.

An alternate process for the production of the instant 17 a-(loweralkyl)-l7B-ols, wherein the alkyl group contains more than one carbonatom, involves the catalytic hydrogenation of the aforementioned17a-alkynyl or 17aalkyl compounds. A dioxane solution of 17a-ethyny1-4-oxa-5a-androstan-175-ol, for example, is shaken in a hydrogen atmospherewith a 5% palladium-on-carbon catalyst to afiord17a-ethyl-4-oxa-5a-androstan-175-01.

The compounds of this invention display valuable pharmacologicalproperties. They are hormonal agents, for example, in view of theirability to produce the physiological efiects typical of androgens.

The invention will appear more fully from the examples United StatesPatent 0 which follow.

Example 1 To a solution of 2 parts of 4-oxa-5a-androstan-l7-one in 40parts of tetrahydrofuran is added 15 parts by volume of a 3 molarethereal methyl magnesium bromide solution, and the resulting mixture isdistilled until about 15 parts by volume of distillate are collected.The resulting reaction mixture is heated at the reflux temperature forabout 4 hours, then is cooled and diluted carefully .with Water in orderto destroy the excess Grignard reagent. An additional 200 parts of waterare then added and the two layers are separated. The aqueous layer isextracted with ether, and this extract is combined with the originalorganic solution. The combined solutions are dried over anhydrous sodiumsulfate and distilled to dryness at reduced pressure. Recrystallizationof the resulting residue from acetone aifords pure 17a-methyl-4-oxa-5a-androstan-17fi-ol, melting at about 19920l. It is represented by thestructural formula OH CH Example 2 Into a slurry of 54 parts of finelydivided potassium hydroxide in 285 parts of diethylene glycol dimethylether containing 15 parts of diethylene glycol monoethyl ether isbubbled gaseous acetylene, at -10, until the mixture becomes saturated.To that mixture is then added a solution of 10 parts of4-oxa-5a-androstan-17-one in 47.5 parts of diethylene glycol dimethylether while the introduction of acetylene is continued and the mixtureis allowed to warm to room temperatur After the reaction has beenallowed to proceed for about 2 hours, the mixture is poured into water,and the resulting precipitate is collected by filtration to yield thecrude product. Recrystallization from ethyl acetate atfords pure17a-ethynyl-4-oxa-5a-androstan-175-01, melting at about 269-271 andcharacterized further by the structural'formula OH CH of an equivalentquantity of propyne Example 2 results in l7a-propynyl-4 The substitutionin the procedure of oxa-ot-androstan-17 3-ol, characterized by thestructural formula Example 4 To a solution of 5 parts ofl7u-ethynyl-4-oXa-5aandrostan-l7fl-ol in 200 parts of pyridine is addedone part of 5% palladium-on-calcium carbonate catalyst, and this mixtureis shaken in a hydrogen atmosphere at one atmosphere pressure until onemolecular equivalent of hydrogen is absorbed. The catalyst is removed byfiltration, and the filtrate is evaporated to dryness at reducedpressure. Recrystallization of the resulting residue from acetoneaffords 17a-vinyl 4 oxa 50c androstan-17f3-ol, melting at about179-180". This substance is represented by the structural formulaExample 5 By substituting 5.23 parts of17oc-propynyl-4-oXa-5aandrostan17/3-ol and otherwise proceedingaccording to the processes described in Example 4, l7a-propenyl-4-oXa-5a-androstan-17B-o1 of the structural formula OH f :L-CH=GHCH3 isobtained.

Example 6 To a solution of 3 parts of17u-ethynyl4-oXa-5etandrostan-17fi-ol in 500 parts of dioxane is added0.5 part of a 5% palladium-on-carbon catalyst, and this mixture isshaken with hydrogen at one atmosphere pressure until two molecularequivalents of hydrogen are absorbed. Removal of the catalyst byfiltration affords a filtrate which is concentrated to dryness bydistillation at reduced pressure. Recrystallization of the resultingresidue from acetone afllords 17a-ethyl 4 oxa 5 a androstan-IZB-ol,

melting at about 157-158. This compound is represented by the structuralformula What is claimed is: 1. A compound of the structural formula OHCH3 L- R o wherein R is selected from the group of radicals consistingof lower alkyl, lower alkenyl, and lower alkynyl.

2. A compound of the structural formula CH3 OH p ---(loweralky1) H 3.17a-methyl-4-oxa-5a-androstan-17 8-01.

4. l7u-ethyl-4-oxa-Sa-androstan-l7,6-01. 5. A compound of the structuralformula OH --(10wer alkynyl) H 6.17a-ethynyl-4-oxa-5ot-androstan-173-01. 7. A compound of the structuralformula OH (lower alkenyl) p 8. 17u-vinyl-4-oXa-5u-androstan-175-01.

No references cited.

1. A COMPOUND OF THE STRUCTURAL FORMULA